Conventional cancer therapy is limited by the problem that the generally attainable targeting ratio (ratio of administered dose of active agent localizing to tumor versus administered dose circulating in blood) is low. This limitation is generally encountered in systemic administration of chemotherapeutic agents as well as in administration of monoclonal antibody-active agent conjugates. Systemic administration involves exposure of healthy tissue to the active agent. Also, as a result of the relatively long half life of a monoclonal antibody, non-target tissue is exposed to circulating antibody-active agent conjugate. Improvement in targeting ratio is therefore sought.
A method employed to improve targeting ratio is referred to generally as pretargeting. In pretargeting, a targeting moiety is formed of a targeting agent and a receptor. The active agent is associated with a ligand for the receptor. The targeting moiety is administered to a recipient, and permitted to localize to the target site with binding at that site mediated by the targeting agent. When target site localization and sufficient elimination of circulating targeting moiety is achieved by the recipient's metabolism, the active agent-ligand is administered. The ligand component of the construct binds to the pretargeted receptor, thereby delivering the active agent to the target.
Pretargeting is made more efficient by administration of a clearing agent to facilitate elimination of circulating targeting moiety. Various clearing agents have been disclosed. Galactose-human serum albumin (HSA)-biotin clearing agents have been employed in pretargeting protocols employing a monoclonal antibody-streptavidin targeting moiety and a biotin-active agent construct. Such clearing agents are discussed in PCT/US93/05406. Derivatization by galactose facilitates elimination of complexes of monoclonal antibody-streptavidin-biotin-HSA-galactose via Ashwell receptors in the liver. These clearing agents rapidly decrease circulating monoclonal antibody-streptavidin levels in patients. Since pretargeting methods are enhanced using clearing agents, improvements in such clearing agents are sought.